Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has demonstrated tremendous potential for treatment of advanced solid tumors. Objective response rates ranging from 34 to 72% have been reported in patients with metastatic melanoma, with durable, complete tumor regression observed in up to 20% of treated patients. However, the current process for isolating, identifying, and expanding therapeutic TIL cells was established more than 30 years ago. TILs are stimulated with a murine anti-CD3 monoclonal antibody (OKT-3), high concentration of recombinant IL-2 produced from E. coli, and irradiated allogeneic or autologous feeder cells. Shortcomings of this process include the need for a surgically resectable tumor as a source of TIL cells, inability to grow TILs for a significant portion of patients, significant presence of regulatory T cells, and long production time. Moreover, TILs are predominantly differentiated into "old" effector T cells in vitro with a terminal phenotype, thereby reducing their long-term survival and antitumor effectiveness in vivo. Younger phenotype T cells, including stem cell memory and central memory T cells, provide superior persistence and antitumor immunity compared with effector memory T cells and effector T cells. This is consistent with recent clinical findings by Dr. Rosenberg and his group that the response of TILs against human cancer is primarily mediated by neoantigen-specific and stem-like CD8+ T cells (CD39-CD69-).Moreover, there is a high unmet need for rapidly progressing cancer types where the window of treatment is limited and where the time for TIL These shortcomings can be surmounted by improving the antibodies and cytokines used ex vivo and optimizing the combination and manufacturing process to robustly and rapidly produce TIL cells, thus, enabling TIL treatment for a broad spectrum of solid tumor patients with higher response rate and curative potential. production becomes of paramount importance. We have been using stably transfected HEK293 cells to produce proprietary antibodies and cytokines. These ancillary materials are critical in TIL manufacturing but are not intended to be part of the final cell product. O ur innovative products for TIL cell production as ex vivo therapeutics have demonstrated striking advantages over current commercial products for TIL production by improving the culture success rate, absolute expansion number, fitness and, critically, shortening the duration of TIL manufacturing while minimizing regulatory T cells. W e have formed a strategic partnership to rigorously evaluate the products and optimize the manufacturing process of TILs. Currently, TILs have been successfully cultured from small tissues of 60 pancreatic and 20 non- pancreatic tumors and scaled up using the Cocoon® Platform (Lonza) for pancreatic tumors, the most difficult TILs to grow so far. Critically, the TILs manufactured in clinical scale has a high frequency of CD8+CD39- CD69- T cells and the reactivities of TILs against neo-antigens were robustly detected by IFNï§ release. The data obtained thus far show a focused, yet diverse TCR repertoire. In addition to a more general TCR analysis in TIL, we were able to link individual TCR clonotypes to individual private target antigens and to trace these back to the TIL product and to the corresponding harvested tumor tissue, respectively. Specific Aim. To determine whether anti-CD137HC and/or IL-12HC enriches antigen-specific T cells and anti- TGFï¢HC, anti-IL-6HC and/or anti-IL-23HC blunts Th17 differentiation and IL-17 release; select top Expi293 cell clones and complete pilot scale production of proprietary antibodies and cytokines critical for TIL manufacturing. The strategic collaborator will validate the efficacy and consistency of our products and pursue regulatory clearance for clinical manufacturing of TILs from pancreatic patients. Importantly, a Phase 1 clinical trial for metastatic or recurrent pancreatic cancer patients has been planned, the first patient is anticipated to be enrolled as soon as 2023.
Public Health Relevance Statement: NARRATIVE We will improve cell-based cancer therapy by optimizing the ex vivo therapeutics and protocol to robustly and rapidly generate tumor antigen-specific infiltrating lymphocytes with younger phenotypes from small tumor biopsies or surgically resected tumors obtained from patients with pancreatic cancer.
Project Terms: Antibodies; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; immunogen; Antigens; Back; Dorsum; Biopsy; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Clone Cells; Endotoxins; Escherichia coli; E coli; E. coli; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Interleukin-2; Co-Stimulator; Costimulator; Epidermal Thymocyte Activating Factor; IL-2; IL2 Protein; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Lymphocyte Mitogenic Factor; Mitogenic Factor; T cell growth factor; T-Cell Growth Factor; T-Cell Stimulating Factor; Thymocyte Stimulating Factor; Lymphocyte Activation; Blast Transformation; Blastogenesis; Lymphoblast Transformation; Lymphocyte Stimulation; Lymphocyte Transformation; Lymphocyte; Lymphatic cell; Lymphocytic; lymph cell; Memory; Mus; Mice; Mice Mammals; Murine; Pancreas; Pancreatic; pancreatic neoplasm; Pancreas Neoplasms; Pancreas Tumor; Pancreatic Tumor; pancreatic neoplasia; Patients; Phenotype; Portugal; Privatization; Production; Recurrence; Recurrent; Relapse; stem cells; Progenitor Cells; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Regulatory T-Lymphocyte; Treg; regulatory T-cells; Time; Tissues; Body Tissues; Transfection; Tumor Antigens; Tumor-Associated Antigen; cancer antigens; tumor-specific antigen; Work; cytokine; Generations; Tumor-Infiltrating Lymphocytes; falls; Mediating; CD3; CD3 Complex; CD3 molecule; OKT3 antigen; T3 Antigens; T3 Complex; T3 molecule; CD3 Antigens; Guidelines; exhaust; cancer progression; neoplasm progression; neoplastic progression; tumor progression; improved; Site; Clinical; Link; Individual; CD8 Cell; CD8 T cells; CD8 lymphocyte; CD8+ T cell; CD8+ T-Lymphocyte; CD8-Positive Lymphocytes; T8 Cells; T8 Lymphocytes; CD8-Positive T-Lymphocytes; Metastatic Melanoma; Solid Tumor; Solid Neoplasm; Letters; Therapeutic; Infiltration; Malignant neoplasm of pancreas; Malignant Pancreatic Neoplasm; Pancreas Cancer; Pancreatic Cancer; pancreatic malignancy; Specimen; Research Specimen; Adoptive Cell Transfers; adoptive cell therapy; adoptive cellular therapy; Frequencies; Autologous; Protocols documentation; Protocol; Source; Tumor Tissue; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; experience; protein purification; success; lymphocyte product; Sterility; sterile; T memory cell; memory T lymphocyte; Reporting; response; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; Effectiveness; IL17 gene; CTLA-8; CTLA-8 Gene; CTLA8; CTLA8 Gene; Cytotoxic T-Lymphocyte-Associated Antigen 8; Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene; Cytotoxic T-Lymphocyte-Associated Serine Esterase 8; Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene; IL-17; IL-17 Gene; IL-17A; IL-17A Gene; IL17; IL17 Protein; IL17A; IL17A Gene; Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8); Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene; Interleukin 17 Precursor; Interleukin 17 Precursor Gene; Interleukin-17; CD8B1 gene; CD8; CD8B; CD8B1; LYT3; fitness; Data; Harvest; Recombinants; Resectable; in vivo; Allogenic; Antigen Targeting; Cancer Center; Enrollment; enroll; Tumor Immunity; anti-tumor immunity; antitumor immunity; cancer immunity; Tumor Promotion; Resected; Process; Pathway interactions; pathway; manufacturing process; scale up; Population; cancer type; Autologous Tumor-Infiltrating Lymphocyte; innovate; innovative; innovation; clinical significance; clinically significant; stem; tumor; T cell response; objective response rate; Checkpoint inhibitor; immune check point inhibitor; Immune checkpoint inhibitor; neo-antigen; neo-epitopes; neoepitopes; neoantigens; antigen-specific T cells; aPD-1; aPD1; anti programmed cell death 1; anti-PD1; anti-programmed cell death protein 1; antiPD-1; antiPD1; aPD-1; aPD1; anti-PD-1; aPD-L1; aPDL1; anti programmed cell death ligand 1; anti programmed cell death protein ligand 1; anti-PD-(L)1; anti-PDL-1; anti-PDL1; antiPD-L1; antiPDL1; aPD-L1; aPDL1; anti-PD-L1; TCR repertoire; T-cell receptor repertoire; therapy optimization; treatment optimization; patients with pancreatic cancer; pancreatic cancer patients; Teff cell; effector T cell; aCTLA-4; aCTLA4; anti-CTLA-4; a-CTLA-4; a-CTLA4; aCTLA-4; aCTLA4; anti-CTLA4; validate efficacy; efficacy validation; Diameter; manufacture
